1. Field of the Invention
The present invention relates to certain dihydropyrimidine, dihydropyrimidone, dihydropyrimidinethione, and dihydropyridine compounds that can modulate the activity of calcium channels. These compounds can also be used for the treatment of diseases, such as cardiovascular disease, that are associated with calcium channels.
2. Description of the Related Art
The pharmacological function and importance of calcium antagonists or calcium channel blockers, has been well documented. See, for example, R. A. Janis and D. J. Triggle “New developments in Ca2+ channel antagonists” Journal of Medicinal Chemistry, 26, 775-785 (1983). Among the calcium antagonists, 4-aryl-1,4-dihydropyridine-3,5-dicarboxylic diesters (DHPs) of the nifedipine type have become almost indispensable for the treatment of cardiovascular diseases. For a review on Structure Activity Relations (SAR) see, S. Goldmann and J. Stoltefuss “1,4-Dihydropyridine: Effects of chirality and conformation on the calcium antagonist and calcium agonist activities” Angewandte Chemie International Edition (English) 30, 1559-1578 (1991). It was well documented that substitution on 4-phenyl ring is very crucial for pharmacological activity. Substituents at ortho or meta position improve the activity, whereas para substitution invariably decrease the activity. It was also published that bulkiness of ortho substituent, improves the calcium antagonist activity. B. Loev, M. M. Goodman, K. M. Snader, R. Tedeschi, E. Macko, “Hantzsch-Type Dihydropyridine hypotensive Agents”, Journal of Medicinal Chemistry 17, 956-965 (1974).
Voltage-gated calcium channels are large transmembrane proteins that regulate the intracellular concentration of calcium ions. They are classified into high (HVA) and low (LVA) voltage-activated channels according to the membrane potential at which they are activated. E. Carbone and H. D. Lux. “A low voltage activated, fully inactivating Ca channel in vertebrate sensory neurons” Nature, 310, 501-502, (1984): B. Nilius, P. Hess, J. B. Lansman and R. W. Tsien A novel type of cardiac calcium channel in ventricular cells. Nature, 316, 443-446. (1985). M. C. Nowycky, A. P. Fox, R. W. Tsien. “Three types of neuronal calcium channels with different calcium agonist sensitivity” Nature 316, 440-443 (1985). LVA channels open and inactivate very fast, but deactivate about 10-100 times slower than HVA calcium channels. HVA channels require stronger membrane depolarizations to activate and can be divided further into N, P/Q,R and L-types based on their pharmacological properties. LVA channels can be detected in various tissues such as heart, brain, dorsal root ganglia and adrenal gland. The use of different search algorithms on mammalian expressed sequence tagged cDNAs or on similar sequences of the nematode Caenorhabditis elegans led to the identification of several genes, three of which encoded LVA calcium channels (T-type channels) and they have been named as α1G, α1H, α1I; see Review, L. Lacinova, N. Klugbauer, F. Hofmann “Low voltage activated calcium channels: from genes to function” Gen. Physiol. Biophys., 19, 121-136, (2000). Of the above stated types of calcium channels, L-type channels received wide attention. Among the L-type channel blockers, Dihydropyridines (DIV) is the most widely studied. But, most of the DHPs are not selective against T-type channels and DHPs inhibiting the T-type channels is still sparse.
Voltage-gated calcium channels are important regulators of calcium influx in a number of cell types. Calcium entry through these channels activates a plethora of intracellular events, from the broad stimulation of gene expression, calcium-dependent second messenger cascades, and cell proliferation, to the specific release of neurotransmitter within the nervous system, and contraction in smooth and cardiac muscle (Tsien et al., 1988) (Wheeler et al., 1994); (Dunlap et al., 1995); (Tsien et al., 1991). A number of different types of calcium channels have been identified in native tissues and divided based on their biophysical profiles into low voltage activated (LVA) and high voltage activated (HVA) channels (Nowycky et al., 1985); (Tsien et al., 1991). LVA channels first activate at relatively hyperpolarized potentials and rapidly inactivate (Akaike et al, 1989); (Takahashi et al., 1991). By contrast, HVA channels require stronger membrane depolarizations to activate and can be divided further into N, P/Q-, R and L-types based on their pharmacological properties (for review, see (Stea et al., 1995); (Zamponi, 1997)). Molecular cloning has revealed that HVA channels are heteromultimers comprised of a pore forming α1 subunit plus ancillary α2-δ, β and possibly γ subunits (Pragnell et al., 1994); (Klugbauer et al., 1999); (Klugbauer et al., 2000); for review, see (Catterall, 2000), whereas LVA channels appear to contain only the α1 subunit (Lacinova et al., 2000)). To date, ten different types of calcium channel α1 subunits have been identified and shown to encode the previously identified native calcium channel isoforms. Expression studies show that alternative splicing of α1A generates both P- and Q-type Ca2+ channels (Bourinet et al., 1999), α1B; encodes N-type channels (Dubel et al., 1992)) α1C, α1D and α1F are L-type channels (Williams et al., 1992b); (Bech-Hansen et al., 1998), α1G, α1H and α1I form T-type channels (i.e., McRory et al., 2001) and α1E may encode R-type channels (Soong et al., 1993); (Totten et al., 1996), and α1S encodes the skeletal muscle L-type channel isoform (Tanabe et al., 1987).
Dihydropyridine (DHP) antagonists of L-type calcium channels are widely used therapeutics in the treatment of hypertension, angina, arrhythmias, congestive heart failure, cardiomyopathy, atheriosclerosis, and cerebral and peripheral vascular disorders (Janis and Triggle, 1990) CRC Press, Cleveland. DHPs having a tendency to selectively block and enhance native L-type calcium channel activity. B. P. (Bean, 1984). B. Z. (Peterson and Catterall, 1995). In addition to L-type channel activity, some of the DHPs are sensitive to T-type channel activity. (N. Akaike, H. Kanaide, T, Kuga, M, Nakamura, J. Sadoshima and Tomoike “Low Voltage Activated Calcium Current in rat Aorta Smooth Muscle Cells In Primary Culture” J Physiol. 416, 141-160, (1989).